: In March 1993, the National Advisory Board on Medical Rehabilitation Research identified "the development of cognitive rehabilitation strategies" in persons with neurological disorders as a high priority research area (HPRA). The present proposal is designed to study the precise mechanism responsible for impaired working memory performance in patients with multiple sclerosis (MS), and to more closely test a rehabilitation strategy previously found by our laboratory to improve working memory in this population. It has long been recognized that persons with MS have deficits in working memory (defined as the ability to simultaneously store and manipulate information in short-term storage). However, preliminary work from our laboratory has shown that, when given enough time to process information, MS subjects perform as well as healthy controls (HCs) on the most commonly used working memory task, the Paced Auditory Serial Addition Test (PASAT). This suggests that persons with MS may not be impaired with regard to working memory at all! Rather, their working memory deficits appear to be primarily attributable to impaired information processing speed. What is still not known, however, is whether increased time for information processing improves MS accuracy on working memory tasks: a) other than the PASAT and b) with varied levels of working memory difficulty. The OVERALL OBJECTIVE of this project is to determine whether increasing the amount of information processing time improves working memory accuracy in MS subjects across tasks with different levels of difficulty. The SPECIFIC AIMS of this project are to: I ) examine the hypothesis that working memory impairment among MS subjects is due to speed of information processing and not accuracy of performance; 2) examine the hypothesis that MS subjects, when given more time to process information, will perform as accurately as HCs on working memory tasks; And 3) extend our initial pilot study by using working memory tasks at various levels of difficulty, thereby increasing the generalizability of our preliminary findings. To investigate these hypotheses, 80 subjects (40 MS and 40 HC) will be administered a variant of the PASAT (also known as the l-back) as well as a more difficult derivative, known as the 2back. In both the 1- and 2-back tasks, accuracy of performance will be controlled at 50 percent correct (by using a computer algorithm utilizing a "method of limits" procedure). This then allows for the quantification of the amount of information processing time required for each subject to achieve accuracy performance of 50 percent correct. To address our aim of increasing the generalizability of our pilot data, we will assess the impact of increased information processing time on performance accuracy on a different working memory task. To achieve this, all subjects will be administered the Salthouse working memory task at 4 levels of task difficulty and with three different amounts of time for information processing (12 different permutations in all). By performing these experiments, we will be able to determine whether increased information processing time is the key cognitive element responsible for deficient working memory performance in patients with MS. Results of this project will have significant implications for the treatment of memory disorders in persons with MS. If our hypotheses are supported, then our data will lay the foundation for intervention strategies geared toward increasing information processing efficiency to improve memory performance in everyday life.